Genetic Variant GRK2:p.Ile32Ile (chr11-67266795-C-T) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP7

The NM_001619.5(GRK2):c.96C>T(p.Ile32Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000665 in 150,442 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 29)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

GRK2
NM_001619.5 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.91

Publications

12 publications found

Variant links:

Genes affected

GRK2 (HGNC:289): (G protein-coupled receptor kinase 2) This gene encodes a member of the G protein-coupled receptor kinase family of proteins. The encoded protein phosphorylates the beta-adrenergic receptor as well as a wide range of other substrates including non-GPCR cell surface receptors, and cytoskeletal, mitochondrial, and transcription factor proteins. Data from rodent models supports a role for this gene in embryonic development, heart function and metabolism. Elevated expression of this gene has been observed in human patients with heart failure and Alzheimer's disease. [provided by RefSeq, Sep 2017]

GRK2 Gene-Disease associations (from GenCC):

Jeune syndrome
Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics

GRK2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.32).

BP7

Synonymous conserved (PhyloP=1.91 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001619.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRK2	NM_001619.5	MANE Select	c.96C>T	p.Ile32Ile	synonymous	Exon 1 of 21	NP_001610.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GRK2	ENST00000308595.10	TSL:1 MANE Select	c.96C>T	p.Ile32Ile	synonymous	Exon 1 of 21	ENSP00000312262.5
GRK2	ENST00000936739.1		c.96C>T	p.Ile32Ile	synonymous	Exon 1 of 21	ENSP00000606798.1
GRK2	ENST00000951317.1		c.96C>T	p.Ile32Ile	synonymous	Exon 1 of 21	ENSP00000621376.1

Frequencies

GnomAD3 genomes

AF:

0.00000665

AC:

AN:

150442

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000201

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1188108

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

583344

African (AFR)

AF:

0.00

AC:

AN:

24194

American (AMR)

AF:

0.00

AC:

AN:

19166

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17858

East Asian (EAS)

AF:

0.00

AC:

AN:

25312

South Asian (SAS)

AF:

0.00

AC:

AN:

47382

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39006

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3382

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

965970

Other (OTH)

AF:

0.00

AC:

AN:

45838

GnomAD4 genome

AF:

0.00000665

AC:

AN:

150442

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73448

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41062

American (AMR)

AF:

0.00

AC:

AN:

15176

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3460

East Asian (EAS)

AF:

0.000201

AC:

AN:

4984

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10184

Middle Eastern (MID)

AF:

0.00

AC:

AN:

310

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67472

Other (OTH)

AF:

0.00

AC:

AN:

2064

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

56660

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Uncertain

0.98

PhyloP100

1.9

PromoterAI

-0.083

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over